VCV000372082.25 - ClinVar

NM_020975.6(RET):c.2393-14C>T

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(7); Likely benign(4)

12 out of 12 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020975.6(RET):c.2393-14C>T

Variation ID: 372082 Accession: VCV000372082.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43119517 (GRCh38) [ NCBI UCSC ] 10: 43614965 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 7, 2017	Mar 16, 2025	Feb 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.2393-14C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001355216.2:c.1631-14C>T		intron variant
NM_001406743.1:c.2393-14C>T		intron variant
NM_001406744.1:c.2393-14C>T		intron variant
NM_001406759.1:c.2393-14C>T		intron variant
NM_001406760.1:c.2393-14C>T		intron variant
NM_001406761.1:c.2264-14C>T		intron variant
NM_001406762.1:c.2264-14C>T		intron variant
NM_001406763.1:c.2258-14C>T		intron variant
NM_001406764.1:c.2264-14C>T		intron variant
NM_001406765.1:c.2258-14C>T		intron variant
NM_001406766.1:c.2105-14C>T		intron variant
NM_001406767.1:c.2105-14C>T		intron variant
NM_001406768.1:c.2129-14C>T		intron variant
NM_001406769.1:c.1997-14C>T		intron variant
NM_001406770.1:c.2105-14C>T		intron variant
NM_001406771.1:c.1955-14C>T		intron variant
NM_001406772.1:c.1997-14C>T		intron variant
NM_001406773.1:c.1955-14C>T		intron variant
NM_001406774.1:c.1868-14C>T		intron variant
NM_001406775.1:c.1667-14C>T		intron variant
NM_001406776.1:c.1667-14C>T		intron variant
NM_001406777.1:c.1667-14C>T		intron variant
NM_001406778.1:c.1667-14C>T		intron variant
NM_001406779.1:c.1496-14C>T		intron variant
NM_001406780.1:c.1496-14C>T		intron variant
NM_001406781.1:c.1496-14C>T		intron variant
NM_001406782.1:c.1496-14C>T		intron variant
NM_001406783.1:c.1367-14C>T		intron variant
NM_001406784.1:c.1403-14C>T		intron variant
NM_001406785.1:c.1376-14C>T		intron variant
NM_001406786.1:c.1367-14C>T		intron variant
NM_001406787.1:c.1361-14C>T		intron variant
NM_001406788.1:c.1208-14C>T		intron variant
NM_001406789.1:c.1208-14C>T		intron variant
NM_001406790.1:c.1208-14C>T		intron variant
NM_001406791.1:c.1088-14C>T		intron variant
NM_001406792.1:c.944-14C>T		intron variant
NM_001406793.1:c.944-14C>T		intron variant
NM_001406794.1:c.944-14C>T		intron variant
NM_020630.7:c.2393-14C>T		intron variant
NC_000010.11:g.43119517C>T
NC_000010.10:g.43614965C>T
NG_007489.1:g.47449C>T
LRG_518:g.47449C>T
LRG_518t1:c.2393-14C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000010.11:43119516:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00140 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00006

1000 Genomes Project 30x 0.00094

1000 Genomes Project 0.00140

Links

ClinGen: CA038910 dbSNP: rs144269978 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RET		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3944	4070

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Multiple endocrine neoplasia type 2B	Benign (2)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV000409467.4
Multiple endocrine neoplasia type 2A	Benign (2)	criteria provided, multiple submitters, no conflicts	Sep 4, 2024	RCV000411041.5
Pheochromocytoma	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2025	RCV001102853.6
Renal hypodysplasia/aplasia 1	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2018	RCV001102854.5
Hirschsprung disease, susceptibility to, 1	Likely benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV001108068.5
Multiple endocrine neoplasia	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV001108069.5
not specified	Likely benign (1)	criteria provided, single submitter	Apr 11, 2019	RCV001002253.8
Multiple endocrine neoplasia, type 2	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 26, 2025	RCV002058857.11

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Apr 11, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001160129.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020

Likely benign (Jan 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001265263.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)

Benign (Jan 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Multiple endocrine neoplasia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001265264.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)

Benign (Jan 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Pheochromocytoma Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001259545.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)

Uncertain significance (Jan 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Renal hypodysplasia/aplasia 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001259546.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)

Benign (May 03, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000489828.2 First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022

Benign (May 03, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Multiple endocrine neoplasia type 2B Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000489827.2 First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022

Benign (Jul 07, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia type 2B Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004017353.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023

Benign (Sep 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018055.2 First in ClinVar: Jul 29, 2023 Last updated: Nov 24, 2024	Comment: This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population … (more) This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)

Likely Benign (Jul 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia, type 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004826179.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 6 Zygosity: Single Heterozygote

Likely benign (Jan 26, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple endocrine neoplasia, type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002370422.4 First in ClinVar: Apr 08, 2022 Last updated: Feb 25, 2025

Benign (Feb 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pheochromocytoma Affected status: no Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV005881254.1 First in ClinVar: Mar 16, 2025 Last updated: Mar 16, 2025

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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs144269978 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.2393-14C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144269978 ...